HISTAMINES AND PUD

Autacoids

i.e. Local hormones; endogenous substances with biological activity.

Histamine, Serotonin

Classification of Autacoids that are Biologically active amines

Prostaglandins, Leukotrienes, Thromboxanes

Classification of autocoids that are lipid derivitive autocoids (Eicosanoids)

Ergot alkaloids

Clasification of autocoids

Kinins, Angiotensin, Endothelin, Natriuretic peptide, Vasopressin, substance P

Classification of autocoids that are Vasoactive polypeptides

Nitric oxide

Classification of autocoids that are Endothelium derived autacoids

Histamine

found in many tissues,including the brain; stored and found in the highest amounts in mast cells and basophils

Immunologic Release

-dependent degranulation reaction; one of process of histamine release

Chemical & Mechanical Release

Occurs following chemical or mechanical injury to mast cells; Displacement is induced by drugs such

morphine, tubocurarine, guanethidine, and amine antibiotics and does not require energy

H1 receptors Location

found in the brain, heart, bronchi, gastrointestinal tract, and vascular smooth muscles.

H2-receptors

Location: found in the brain, heart, vasculature, and parietal cells

Histamine

R-alpha methylhistamine is an H3-specific agonist. (Histamine agonist)

Betazole (histalog)

tenfold greater activity at H2-receptors than at

H1-receptors (histamine agonist)

Impromidine

investigational agent; its ratio of H2:H1 activity

is about 10,000 (histamine agonist)

USES OF HISTAMINE AGONISTS

- allergy testing to assessMhistamine sensitivity

- test of gastric secretory function

- function (they have been largely supplanted for this use by pentagastrin)

Adverse effects of HISTAMINE AGONISTS

- Flushing

- Hypotension

- Tachycardia

- Headache

- Wheals

- Bronchoconstriction

- Gastrointestinal upset

Histamine (H1)-receptor antagonists

Aka : classical ANTIHISTAMINES; competitive inhibitors at the H1- receptor.

Ethanolamines

- anti emetics

- Carbonoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine (sleeping aid)

- 1st generation antihistamine (H1 receptor antagonist/blocker)

Ethylaminediamines

- produce moderate sedation and can cause gastrointestinal upset

- Pyrilamine, Tripelennamine

- 1st generation antihistamine (H1 receptor antagonist/blocker)

Piperazine

- Antiemetics, anti-motion sickness

- Hydroxyzine, Cyclizine, Meclizine

- 1st generation antihistamine (H1 receptor antagonist/blocker)

Alkylamines

- brompheniramine, chlorpheniramine (agents which produce slight sedation)

- 1st generation antihistamine (H1 receptor antagonist/blocker)

Phenothiazines

- Promethazine (antiemetic)

- weak alpha-adrenoceptor antagonist.

- 1st generation antihistamine (H1 receptor antagonist/blocker)

Cyproheptadine

- antihistamine, anticholinergic, and antiserotonin activities

- Miscellaneous 1st generation antihistamine (H1 receptor antagonist/blocker)

Piperidines

- Terfenadine (Seldane), Fexofenadine, Astemizole (Hismanal) (AE: ventricular tachycardia)

- 2nd generation antihistamine (H1 receptor antagonist/blocker)

Loratidine, Cetirizine

- Poor CNS penetration, less sedating

- Miscellaneous 2nd generation antihistamine (H1 receptor antagonist/blocker)

Pharmacokinetic Properties of H1 Blocking Drugs

well absorbed after oral administration.; Normal effects seen in 30 minutes (with maximal effects at 1-2 hours)

3-6 hours

The duration of action of 1st generation H1 Blocking Drugs

3-24 hours

The duration of action of 2nd generation H1 Blocking Drugs

H1-receptor antagonists/ Antihistamines

- lipid-soluble = cross the blood-brain barrier

- metabolized in the liver; many induce microsomal enzymes and

alter their own metabolism

ANTICHOLINERGIC activity

- block mucus secretion and sensory nerve stimulation.

-ethanolamine, phenothiazines, and ethylenediamines

local anesthetics

Eg. Dimenhydrinate and promethazine

Pharmacologic Actions of H1-receptor antagonists

- relax histamine-induced contraction of bronchial smooth muscle and have some use in allergic bronchospasm.

- block the vasodilator action of histamine.

- inhibit histamine-induced increases in capillary permeability.

- frequently cause CNS depression (marked by sedation, decreased alertness, and decreased appetite)

- In children and some adults, these agents stimulate the CNS.

Therapeutic uses of H1-receptor antagonists

- Treatment of allergic rhinitis and conjunctivitis.

- treat the common cold based on their anticholinergic properties

- Treatment of urticaria and atopic dermatitis, including hives

- Sedatives

- Prevention of motion sickness

- Appetite suppressants

Diphenydramine

also has an antitussive effect not mediated by H1-receptor antagonism.

Sedatives

Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids.

Adverse Effects of H1 - receptor antagonists

- sedation (synergistic w/ alcohol, other depressants, dizziness, and loss of appetite. CAUTION: drivers and machine operators

- gastrointestinal upset, nausea, constipation and diarrhea.

- anticholinergic effects (dry mouth, blurred vision, and urine retention).

Histamine (H2)-receptor antagonists

- competitive antagonists at the H2- receptor, which predominates in the gastric parietal cell.

- Cimetidine (Tagamet), Ranitidine (Zantac), Famotidine (Pepcid AC), Nizatidine (Axid)

Uses of H2-receptor Antagonists

- treatment of gastrointestinal disorders

- heartburn and acid-induced indigestion

- promote the healing of gastric and duodenal ulcers

- hypersecretory states such as Zollinger-Ellison syndrome

Inhibitors of histamine release

- poorly absorbed salts; ROUTE of admin: inhalation

- They inhibit the release of histamine and other autacoids from the mast cell. (increase influx of Chloride ions)

- Prophylactic agents in asthma

- Nedocromil sodium

- adverse effects: sore throat and dry mouth

Nedocromil sodium

appears to be more effective in reducing bronchospasm caused by exercise or cold air.

Peptic Ulcer

circumscribed loss of the mucous

membrane of the GIT system

duodenal ulcer

- gnawing or burning upper abdomen pain relieved by food

- manifested by hematemesis and melena

Gastirc ulcer

- Relieved by food but may persist

- anorexia, wt loss and vomiting

- severe ulcer may erode through stomach wall

Imbalance

The reason why ulceration occurs primarily between aggressive factors and defensive factors

Helicobacter pylori

Gram (-) flagella that is the most common cause of PUD; secretes urease, produces alkalone environment and is considered a class 1 carcinogen

NSAIDs

Damage to the cytiprotectivemrole of PGs-PGE2 and PGI2

signs and symptoms of doudenal ulcers

- gnawing, burning or aching pain (tends to

worsen at night and occurs 1-3 hours after meals)

-nausea, vomiting, belching and significant

weight loss.

Bleeding Complications of PUD

- occurs in 25-33%of patients; most frequent complication and maybe life-threatening

- account for 25% of ulcer deaths; may be the first indication of an ulcer

Perforation Complications of PUD

- occurs in about 5% of the patients; accounts for 2/3 of ulcer deaths

Obstruction from edema or scarring Complications of PUD

- often due to pyloric channel ulcers; occur with duodenal ulcer

- causes incapacitating , crampy abdominal pain; may lead to total obstruction with

Goal of therapy with anti-ulcer drugs

1. reduce gastric acid production

2. neutralize gastric PH

3. protect the walls of the stomach from the

acid and pepsin released by the stomach

4. treat peptic ulcer and reflux esophagitis

ANTACIDS

Acid Neutralizing agents

Sodium Bicarbonate and Sod. Citrate

Systemic antacids

Magnesium hydroxide, Mag. Treisilicate, Aluminium, hydroxide gel, Magaldrate and calcium carbonate

Nonsystemic anta acid

Cimetidine, Ranitidine, Famotidine, Nizatidine and Roxatidine

H2 antihistamines:

Omeprazole, Lansoprazole,Pantoprazole, Rabeprazole and Esomeprazole

Proton pump inhibitors

Pirenzepine, Propantheline and Oxyphenonium

Anticholinergics

Misoprostol

Prostaglandin analogue

Sucralfate, Colloidal,Bismuth sudcitrate

Ulcer protectives

Amoxicillin,Clarithromycin, metronidazole, tinidazole and tetracycline

Anti-H. pylori Drugs

H2 receptor antagonists

- "tidine"

Cimetidine

Ranitidine

Nizatidine

Famotidine

H2 receptor antagonists MOA

decrease gastric acid secretion through competitive

inhibition of H2 receptors

H2 receptor antagonists USES

- GERD

- Duodenal and gastric ulcer

- non-ulcer dyspepsia

- prophylaxis for recurrent ulcers in patients

- control of reflux esophagitis and bile reflux

gastritis

- prevent aspiration pneumonia

- Hypersecretory states

Cimetidine

- H2 receptor antagonist that reduces acid secretion by 70% for 4-5 hours (300mg qid); bioavailability is reduced by antacids

- decreases the absorption of ketoconazole; Potent inhibitor of CYP450 IV : dementation and bradycardia (elderly)

Ranitidine

- H2 receptor antagonist that is five to ten times more

potent than cimetidine; does not bind to androgen receptor

- secreted in milk therefore it should not be given in lactating mothers

- low incidence of headache and cutaneous rash; hepatotoxic

Famotidine

- H2 receptor antagonist that is approximately twice as potent as ranitidine; Most potent H2 blocker

- tachyphylaxis compromise its long term use; has a longer duration of action

- -produces fewer side effects similar to those of ranitidine; mild cardiotoxic

Nizatidine

- H2 receptor antagonist that is as effective as ranitidine and may be administered once daily

- may produce hepatotoxicity but it does not inhibit drug metabolism in the absence of liver damage; does not bind to androgen receptors

Proton pump inhibitors (PPI's)

- "prazole"

Omeprazole

Lansoprazole

Rabeprazole

Pantoprazole,

Esomeprazole

Proton pump inhibitors (PPI's) USES

- GERD

- Duodenal and gastric ulcer. H.pylori ulcer,

NSAID-induced ulcer

- Prevention of rebleeding from peptic ulcer

- non-ulcer dyspepsia

- Prevention of stress-related mucosal bleeding

- Gastrinoma and Hypersecretory states

Omeprazole

- Proton pump inhibitors (PPI's) that is given as delayed release capsule because of acid lability

- antisecretory effects occurs within 1 hour with the maximum effects occurring within 2 hours; may produce abdominal pain, nausea, diarrhea, vomiting, rash, constipation, headache, asthenia and back pain

- may inhibit the metabolism of warfarin,cdiazepam, and phenytoin; inhibits the absorption of ketoconazole contraindicated in pregnancy

Lansoprazole

- Proton pump inhibitors (PPI's) acid labile and administered as an enteric coated tablet; prodrug that requires protonation for activation

- most effective when given 30 to 60 mins before meals; its acid inhibitory effects is greater than 24 hours

- adverse effects include abdominal pain, nausea

and diarrhea; can increase theophylline clearance and contraindicated in asthma

Sucralfate

- Cytoprotective agents, a salt of sucrose complexed to sulfated aluminum hydroxide

- has an affinity for exposed proteins in the crater of peptic ulcer

- protects ulcerated areas from further damage and promotes healing

Sucralfate MOA

- stimulates mucosal production of prostaglandins and inhibits pepsin

- may produce constipation and nausea, gastric discomfort, indigestion, dry mouth, rash, pruritus, back pain, dizziness, sleepiness and vertigo, hypophosphatemia

Sucralfate - contd.

- Taken on empty stomach 1 hr. before meals

- Concurrent antacids, Hz antagonist avoided (as it needs acid for activation)

Uses:

- NSAID induced ulcers

- Patients with continued smoking

- ICU

Topically - burn, bedsore ulcers, excoriated skins

Dose: 1 gm 1 Hr before meals

Misoprostol

- Cytoprotective agents, A prostaglandin E1

analog

- more water soluble and it has a half-life than naturally occurring prostaglandin

- inhibits gastric acid secretion and increases mucosal resistance

Misoprostol MOA

increases mucus and bicarbonate secretion by the gastric epithelium by increasing epithelial regeneration and by enhancing mucosal blood flow, thus enhancing mucosal protection; produces uterine contractions therefore contraindicated in pregnancy

Colloidal Bismuth Compounds

- bismuth subsalicylate

- bismuth subcitrate

- bismuth dinitrate

Colloidal Bismuth Compounds MOA

coats ulcers and erosions, creating a protective layer against acid and pepsin; It may also stimulate prostaglandin, mucus, and bicarbonate secretion

Bismuth

- has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler's diarrhea.

- direct antimicrobial activity against H pylori

Bismuth Clinical Uses

- nonspecific treatment of dyspepsia and acute diarrhea

- prevention of traveler's diarrhea (30 mL or 2 tablets four times daily)

- for the eradication of H pylori infection

Bismuth Adverse Effects

- causes blackening of the stool

- Liquid formulations may cause harmless darkening of the tongue.

- Bismuth agents should be used for only short periods and should be avoided in patients with renal insufficiency.

- bismuth toxicity resulting in encephalopathy

(ataxia, headaches, confusion, seizures).

Carbenoxolone

- synthetic derivative of glycyrrhizic acid; heals both gastric and duodenal ulcers

Carbenoxolone MOA and A/E

- increases production, secretion and viscosity of intestinal mucus

A/E: Aldosterone effect

Antacids (cont'd)

Antacids (cont'd)

Nonsystemic antacids

Aluminum hydroxide (Amphojel)

Dihyroxyalumium sodium (Rolaids)

Calcium carbonate (Tums)

Magaldrate (Riopan)

Magnesium hydroxide and aluminum

hydroxide (Maalox, Mylanta, Gelusil)

Dosing interval of Antacid

Ideal antacid should be rapid in onset and

provide a continuous buffering action

Rapid onset

Mg(OH)2, MgO, CaCO3

Slow onset

Mg trisilicate and aluminum compounds

Duration of buffering action of antacid

- determined by the administration of antacid

- With food: action will last for 2 hr

- An additional 3 hr meals will extend the buffering time by 1 hr

- Ideal dosing interval: 1 and 3 hr aftermeals and at bedtime

Side effects of SSRIs

- Sodium bicarbonate Soluble and readily absorbed

- Can cause electrolyte disturbance and alkalosis

Side effects of Non- systemic antacids

Al, Ca, Mg Form insol compounds in the GIT

Patients with increase risk of antacid toxicity

- Heart failure = excess sodium intake (inc. toxicity)

- Renal failure = should not use magnesium containing antacids ( can cause hypermagnesemia) or sodium bicarbonate ( systemic alkalosis)

= given with aluminum containing antacids for

their phosphate lowering effect

Sodium bicarbonate

Antacid that is absorbed systemically and should not

be used for long-term treatment; contraindicated to hypertension due to its high sodium content

Sodium Bicarbonate

- Potent neutralizing capacity and acts instantly

- ANC: 1 gm = 12 mEq

NOT USED ANYMORE FOR ITS DEMERITS:

- Systemic alkalosis

- Distension, discomfort and belching - COz

- Rebound acidity

- Sodium overload

Calcium carbonate

- antacid that partially absorbed from the gastrointestinal tract and have some systemic effects should not be used for long term use

- may stimulate gastrin release and thereby cause rebound acid production contraindicated in renal disease

ADR of Calcium carbonate

Hypercalcemia, Alkalosis, Renal failure (milk-alkali syndrome)

Magnesium hydroxide

- antacid that not absorbed in the GIT therefore produces no systemic effects; can be used for long term therapy may produce diarrhea

- Magnesium containing preparation ( Diarrhea, Hypermagnesemia)

Aluminum hydroxide

Antacid that has no systemic effects and causes constipation; Also hypophosphatemia and osteomalacia

Prolonged Aluminum use

Phosphate depletion Osteoporosis, osteomalacia,, neurotoxicity

Combination products

- various preparations that combine magnesium hydroxide and aluminum hydroxide

- to achieve a balance between agents adverse effects on the bowel.

- Examples of which are Maalox, Mylanta and Gelusil.

Simethicone

- Not an antacid

- Used to defoam gastric juice to decrease

the incidence of gastroesophageal reflux